Long-Term Management of Patients at Risk of Atherothrombosis

1. Long-Term Management of Patients at Risk of Atherothrombosis Section 3The Role of Platelets in Atherothrombotic Disease This section demonstrates how platelets play a key role in atherothrombotic events � both in the acute and long term. This section demonstrates how platelets play a key role in atherothrombotic events � both in the acute and long term.

2. Hemostatic Plug Formation Hemostasis � �the termination of bleeding by mechanical or chemical means or by the complex coagulation process of the body, which consists of vasoconstriction, platelet aggregation and thrombin and fibrin synthesis�.1 Primary hemostasis is the name given to the process of platelet-plug formation at sites of injury. It occurs within seconds of injury and is of prime importance in stopping blood loss.2 Secondary hemostasis describes the reactions of the plasma coagulation system which results in fibrin formation. It takes several minutes before this process is completed. The fibrin strands strengthen the primary hemostatic plug. This reaction is particularly important in larger vessels to prevent recurrent bleeding hours or days after the initial injury.2 Although presented here as separate events, primary and secondary hemostasis are closely linked. For example, activated platelets accelerate plasma coagulation, and products of the plasma coagulation reaction, such as thrombin, stimulate platelet aggregation.2 Hemostasis � �the termination of bleeding by mechanical or chemical means or by the complex coagulation process of the body, which consists of vasoconstriction, platelet aggregation and thrombin and fibrin synthesis�.1 Primary hemostasis is the name given to the process of platelet-plug formation at sites of injury. It occurs within seconds of injury and is of prime importance in stopping blood loss.2 Secondary hemostasis describes the reactions of the plasma coagulation system which results in fibrin formation. It takes several minutes before this process is completed. The fibrin strands strengthen the primary hemostatic plug. This reaction is particularly important in larger vessels to prevent recurrent bleeding hours or days after the initial injury.2 Although presented here as separate events, primary and secondary hemostasis are closely linked. For example, activated platelets accelerate plasma coagulation, and products of the plasma coagulation reaction, such as thrombin, stimulate platelet aggregation.2

3. Platelet Adhesion and Activation Platelets (Diagram 1) platelets perform a very important biologic role in the vascular system. Interaction between the platelet and vessel wall are of crucial importance in physiology and pathophysiology. under normal circumstances, platelets do not adhere to healthy arterial walls nor are they activated by the vascular endothelium. However, at the site of injury, such as that caused by a ruptured atherosclerotic plaque, platelets will adhere to the endothelium, become activated and trigger the recruitment of more platelets forming a platelet plug. Platelet adhesion (Diagram 2) within a few seconds of injury, platelets adhere to collagen fibrils in vascular subendothelium via a specific platelet collagen receptor made up of glycoproteins. This interaction is stabilized by the von Willebrand factor, an adhesive glycoprotein which allows platelets to remain attached to the vessel wall despite the high shear forces generated within the vascular lumen. Platelet aggregation is mediated by fibrinogen which links adjacent platelets on the platelet glycoprotein IIb/IIIa complex. Platelet activation (Diagram 3) Platelets can be activated by many mechanisms. Most of the substances released by these cells � in particular adenosine diphosphate, serotonin, thromboxane and others � can, in an autocrine and paracrine fashion, further enhance platelet activation and aggregation. Under these conditions there is also activation of the coagulation cascade; therefore thrombin is formed, which also markedly stimulates platelet activation.Platelets (Diagram 1) platelets perform a very important biologic role in the vascular system. Interaction between the platelet and vessel wall are of crucial importance in physiology and pathophysiology. under normal circumstances, platelets do not adhere to healthy arterial walls nor are they activated by the vascular endothelium. However, at the site of injury, such as that caused by a ruptured atherosclerotic plaque, platelets will adhere to the endothelium, become activated and trigger the recruitment of more platelets forming a platelet plug. Platelet adhesion (Diagram 2) within a few seconds of injury, platelets adhere to collagen fibrils in vascular subendothelium via a specific platelet collagen receptor made up of glycoproteins. This interaction is stabilized by the von Willebrand factor, an adhesive glycoprotein which allows platelets to remain attached to the vessel wall despite the high shear forces generated within the vascular lumen. Platelet aggregation is mediated by fibrinogen which links adjacent platelets on the platelet glycoprotein IIb/IIIa complex. Platelet activation (Diagram 3) Platelets can be activated by many mechanisms. Most of the substances released by these cells � in particular adenosine diphosphate, serotonin, thromboxane and others � can, in an autocrine and paracrine fashion, further enhance platelet activation and aggregation. Under these conditions there is also activation of the coagulation cascade; therefore thrombin is formed, which also markedly stimulates platelet activation.

4. Platelet Aggregation Platelet shape Flowing disk-shaped platelets become ball-shaped on interaction with von Willebrand factor via the glycoprotein Ib receptor. This interaction starts the platelet rolling, releasing �inside out� signals, promoting change to a hemispherical shape. This increases the surface area of the platelet in contact with the vessel surface and helps the platelet to resist rapid blood flow which could dislodge it from the surface. At this point, platelets do stop on the vessel surface, but adhesion is still reversible. Further activation via �outside-in� signaling leads to irreversible platelet adhesion and extensive spreading, generating a greater thrombogenic base to capture further platelets to aggregate on the surface.1 Platelet aggregation Platelets themselves are now recognized as a source of inflammatory mediators rather than just responders to thrombotic stimuli. Inflammation can give rise to local thrombosis which can amplify inflammation. Anti-inflammatory therapies (such as ASA) may therefore limit thrombosis and antithrombotic therapies may reduce vascular inflammation, thereby breaking the vicious cycle of acute coronary syndromes.2Platelet shape Flowing disk-shaped platelets become ball-shaped on interaction with von Willebrand factor via the glycoprotein Ib receptor. This interaction starts the platelet rolling, releasing �inside out� signals, promoting change to a hemispherical shape. This increases the surface area of the platelet in contact with the vessel surface and helps the platelet to resist rapid blood flow which could dislodge it from the surface. At this point, platelets do stop on the vessel surface, but adhesion is still reversible. Further activation via �outside-in� signaling leads to irreversible platelet adhesion and extensive spreading, generating a greater thrombogenic base to capture further platelets to aggregate on the surface.1 Platelet aggregation Platelets themselves are now recognized as a source of inflammatory mediators rather than just responders to thrombotic stimuli. Inflammation can give rise to local thrombosis which can amplify inflammation. Anti-inflammatory therapies (such as ASA) may therefore limit thrombosis and antithrombotic therapies may reduce vascular inflammation, thereby breaking the vicious cycle of acute coronary syndromes.2

5. Key Mediators in Platelet Adhesion, Activation and Aggregation At the site of arterial injury, the endothelial barrier is broken and platelets adhere to exposed collagen, von Willebrand factor (vWF), and fibrinogen via specific cell receptors. Adherent platelets are then activated by several independent mediators, including collagen, thromboxane, adenosine diphosphate (ADP), and thrombin. Activated platelets degranulate and secrete chemotaxins, clotting factors and vasoconstrictors, thereby promoting thrombin generation, vasospasm, and additional platelet accumulation. The release of internally stored ADP and thromboxane amplifies the process of platelet activation by secondary feedback loops. Activated platelets also change shape resulting in cell membrane changes, which are important in further aggregation and coagulation. Previously inactive GPIIb/IIIa receptors on the platelet membrane undergo structural modification and become available for fibrinogen and vWF binding. In patients with atherosclerotic stenosis, shear stress can be abnormally elevated and can directly activate platelet aggregation and/or amplify all of the three platelet steps, mediated through vWF and ADP-receptors.At the site of arterial injury, the endothelial barrier is broken and platelets adhere to exposed collagen, von Willebrand factor (vWF), and fibrinogen via specific cell receptors. Adherent platelets are then activated by several independent mediators, including collagen, thromboxane, adenosine diphosphate (ADP), and thrombin. Activated platelets degranulate and secrete chemotaxins, clotting factors and vasoconstrictors, thereby promoting thrombin generation, vasospasm, and additional platelet accumulation. The release of internally stored ADP and thromboxane amplifies the process of platelet activation by secondary feedback loops. Activated platelets also change shape resulting in cell membrane changes, which are important in further aggregation and coagulation. Previously inactive GPIIb/IIIa receptors on the platelet membrane undergo structural modification and become available for fibrinogen and vWF binding. In patients with atherosclerotic stenosis, shear stress can be abnormally elevated and can directly activate platelet aggregation and/or amplify all of the three platelet steps, mediated through vWF and ADP-receptors.

6. Plaque Disruption Leading to Atherothrombosis Formation The hemostatic process to form a thrombus is not uniform � size and composition of the blood clot varies with the site of injury. The result of plaque rupture and consequent thrombus formation can therefore be an acute event (such as myocardial infarction), or contribute to the long-term underlying progression of vascular disease. A large fissure typically results in the formation of a large thrombus that completely occludes the vessel resulting in an acute vascular event. A smaller fissure may result in a mural thrombus that partially or transiently occludes the artery, causing acute ischemia and contributing to the progressive process of plaque growth.The hemostatic process to form a thrombus is not uniform � size and composition of the blood clot varies with the site of injury. The result of plaque rupture and consequent thrombus formation can therefore be an acute event (such as myocardial infarction), or contribute to the long-term underlying progression of vascular disease. A large fissure typically results in the formation of a large thrombus that completely occludes the vessel resulting in an acute vascular event. A smaller fissure may result in a mural thrombus that partially or transiently occludes the artery, causing acute ischemia and contributing to the progressive process of plaque growth.

7. Inflammatory Modulators Produced by Platelets Although physicians acknowledge the key function of platelets in arterial thrombosis, most relegate platelets to a limited role as a responder to thrombotic stimuli. However, recent studies attribute an important regulatory role to the platelets as a source of inflammatory mediators:1 Platelet-factor 4 which belongs to a CXC chemokine family of inflammatory modulators; can mediate shear-resistant arrest of monocytes to endothelium1 Deposition of RANTES by platelets triggers shear-resistant monocyte arrest on inflamed or atherosclerotic endothelium and may thereby play a pivotal role in the pathogenesis of inflammatory and atherosclerotic disease2 Nitric oxide is a principal factor involved in the anti-atherosclerotic properties of the endothelium; interferes with monocyte and leucocyte adhesion to the endothelium, as well as platelet-vessel interaction; it has been shown to inhibit vascular smooth cell proliferation and migration3 CD154 (CD40 ligand) has been found in atheroma-associated cells and ligation of CD40 has been shown to regulate smooth muscle and endothelial cell functions relevant for the pathogenesis of atherosclerosis1,4 Thrombospondin: interacts with different cell surface receptors.1 Although physicians acknowledge the key function of platelets in arterial thrombosis, most relegate platelets to a limited role as a responder to thrombotic stimuli. However, recent studies attribute an important regulatory role to the platelets as a source of inflammatory mediators:1 Platelet-factor 4 which belongs to a CXC chemokine family of inflammatory modulators; can mediate shear-resistant arrest of monocytes to endothelium1 Deposition of RANTES by platelets triggers shear-resistant monocyte arrest on inflamed or atherosclerotic endothelium and may thereby play a pivotal role in the pathogenesis of inflammatory and atherosclerotic disease2 Nitric oxide is a principal factor involved in the anti-atherosclerotic properties of the endothelium; interferes with monocyte and leucocyte adhesion to the endothelium, as well as platelet-vessel interaction; it has been shown to inhibit vascular smooth cell proliferation and migration3 CD154 (CD40 ligand) has been found in atheroma-associated cells and ligation of CD40 has been shown to regulate smooth muscle and endothelial cell functions relevant for the pathogenesis of atherosclerosis1,4 Thrombospondin: interacts with different cell surface receptors.1

8. Role of PlateletsSummary Rupture or erosion of an atherosclerotic plaque exposes the thrombogenic core of the lesion and lead to adhesion and aggregation of platelets and thrombus formation1 A large rupture typically results in the formation of a large thrombus that completely occludes the vessel, resulting in an acute vascular event2 A smaller rupture may result in a mural thrombus that partially or transiently occludes the artery, causing acute ischemia and, in the long term, contributing to progression of atherothrombosis2 Platelets produce several inflammatory modulators and may play a significant role in atherosclerotic development3 Rupture or erosion of an atherosclerotic plaque exposes the thrombogenic core of the lesion and lead to adhesion and aggregation of platelets and thrombus formation.1 A large rupture typically results in the formation of a large thrombus that completely occludes the vessel, resulting in an acute vascular event.2 A smaller rupture may result in a mural thrombus that partially or transiently occludes the artery, causing acute ischemia and, in the long term, contributing to progression of atherothrombosis.2 Platelets produce several inflammatory modulators and may play a significant role in atherosclerotic development.3Rupture or erosion of an atherosclerotic plaque exposes the thrombogenic core of the lesion and lead to adhesion and aggregation of platelets and thrombus formation.1 A large rupture typically results in the formation of a large thrombus that completely occludes the vessel, resulting in an acute vascular event.2 A smaller rupture may result in a mural thrombus that partially or transiently occludes the artery, causing acute ischemia and, in the long term, contributing to progression of atherothrombosis.2 Platelets produce several inflammatory modulators and may play a significant role in atherosclerotic development.3

10. Disclaimer This slide kit presents data to support the rationale for the use of ADP-receptor antagonists in registered and non-registered indications. The slide kit has been prepared for medical and scientific purposes, and cannot be considered as an inducement to use clopidogrel in non-registered indications. Neither Sanofi-Synth�labo nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.